Novel steroidal antiestrogens and antiandrogens and uses thereof

ABSTRACT

The present invention comprises the design, synthesis and development of a new class of chemotherapeutic agents for prophylactic and therapeutic treatments in a mammal, particularly a human, believed to be at risk of suffering from a hormone-responsive disorder. In an embodiment of the invention, such treatments include therapeutic compositions comprising novel steroidal antiestrogen and antiandrogen compounds. In a preferred embodiment, such a novel compound of the present invention has an address and a message component, which are made into a single composite entity for more aggressive intervention and effective treatment of hormone-responsive disorders, thereby prolonging the disease-free interval for the patient and reducing a number of side effects.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims the priority benefit of provisional U.S. PatentApplication No. 60/213,282, filed Jun. 22, 2000 entitled, NOVELSTEROIDAL ANTIANDROGENS AND USES THEREOF, the whole of which is herebyincorporated herein by reference.

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

Part of the work leading to this invention was carried out with UnitedStates Government support provided under a grant from the NationalInstitutes of Health, Contract Number 1R01CA81409. Therefore, the UnitedStates Government has certain rights in this invention.

BACKGROUND OF THE INVENTION

Antagonists to both estrogen and androgen receptors have been developedfor the treatment of hormone-related conditions. For example,antiestrogenic agents are useful for the treatment of breast cancer andantiandrogenic agents are useful for the treatment of prostate cancer.

Breast cancer, at 182,000 cases per year, is the most common cancerdiagnosis among women in the United States, accounting for over 40,000deaths annually (Greenlee, 2000). It is estimated that one in eightwomen will develop breast cancer during their lifetime and one in threeof those will die from the disease. Of those women diagnosed with breastcancer, approximately 60% have tumors that are classified ashormone-responsive, meaning that the tissue contains elevated levels ofthe estrogen receptor and the tumor cell proliferation is stimulated bycirculating estrogens (Scott, 1991). Various available treatmentsinclude surgery (e.g., lumpectomy, mastectomy or modified radicalmastectomy, which removes the breast and underlying muscle along withadjacent lymph nodes), radiation, chemotherapy or biological treatments.

Hormonal therapy characterized as either removal of estrogen producingtissues, inhibition of estrogen biosynthesis or blockade of estrogenreceptors by antagonists (e.g., tamoxifen (Nolvadex®) and Faslodex®,raloxifene, and idoxifene), has been shown to produce a positiveobjective response (Beatson, 1896; Boyd 1900; Bhatanagar, 1999; Cole,1971; and Lancet 351, 1998). Such interventions, however, are oftenaccompanied by major side effects that are tolerated because of theparticular risks associated with the primary disease. Over the past 10years, studies with antiestrogens structurally related to tamoxifen havedemonstrated that some of the side effects can be ameliorated, dependingupon the features incorporated within the structure of the drug. Agentsthat may block cancer cell proliferation (antagonism) withouteliminating the beneficial effects on bone density and cardioprotectionhave been termed Selective Estrogen Receptor Modulators (SERMs) (Grese;Levenson, 1999). Known non-steroidal antagonists that are tamoxifen-likeand raloxifen-like display antiestrogen effects in some tissues andestrogen-like effects in others. These SERMs may be beneficial for thetreatment of hormone responsive cancers (or potentially as prophylacticagents) without causing osteoporosis or increasing the risk forcardiovascular disease. However, their receptor affinity is generallyless than that of estradiol, and because they have a non-steroidalstructure, they often exhibit additional, non-hormonal effects.Additionally, hormone responsive cancers progress to a stage where theybecome hormone-independent, requiring a subsequent, more aggressiveapproach.

Prostate cancer is the most common cancer diagnosis among American men(29%) and the second leading cause of death due to cancer (13%) (Landis,1999; Haas, 1997; Mettlin, 1997). Like breast cancer in women, most ofthe newly diagnosed cases are hormone responsive and patients experiencea reduction in tumor growth or regression with antihormone(antiandrogen) therapy (Roach, 1999).

Hormonal therapy is often used in all phases of prostate cancertreatment to help block production or action of the male hormones thathave been shown to fuel prostate cancer. Antiandrogens are divided intotwo groups: steroidal and non-steroidal. Among widely used approvedhormone blockers, often used in combination, are Casodex (bicalutamide),Eulexin (flutamide), Anandron (nilutamide), LG 120907, which arenonsteroidal (see FIG. 9), and Lupron (leuprolide acetate), and Zoladex(goserelin acetate implant), which are peptides that block GnRH release.The nonsteroidal antiandrogens can be displaced by endogenous ligands,i.e., dihydrotestosterone. Therefore, these antiandrogens have not beenas successful in the treatment of prostate cancer due to theirreversability in binding to the androgen receptor. Some studies havesuggested that dihydrotestosterone bromoacetate (DHT-BA) bindsirreversibly to the androgen receptor (AR). However, other studies showthat DHT-BA apparently binds to aldehyde dehydrogenase and not to the AR(McCammon, 1993). Therefore, DHT-BA is not as optimal in the treatmentof prostate cancer.

Because the testicles produce male hormones, some men also undergotesticle removal to cut off the hormone supply. Advanced prostate cancerpatients are usually treated with any number of chemotherapeutic drugssuch as Novantrone (mitoxantrone), which do not cure the disease butoften do ease pain and other symptoms. However, within one to threeyears of such therapy, there is often recurrence of disease in which thetumor has acquired hormone independence (Galbraith, 1997). At thispoint, antiandrogen therapy becomes much less effective and a moreaggressive intervention is required (Ornstein, 1999). A second issue isthat current antiandrogen therapy, even when effective, elicits a numberof side effects (e.g., impotence, incontinence, loss of libido,gynecomastia, heat intolerance, or hot flashes) that compromise thepatient's quality of life.

Therefore, the development of more therapeutically effectiveantiestrogenic and antiandrogenic agents that target hormone-dependenttumors would: (1) provide a substantial benefit for the initialreduction of disease, (2) provide a prolonged disease-free interval, (3)improve the long term prognosis, and (4) reduce the incidence andseverity of the side effects.

BRIEF SUMMARY OF THE INVENTION

The present invention encompasses both prophylactic and therapeutictreatments for a mammal, preferably a human, at risk for ahormone-responsive disorder. In particular, the therapeutic compounds,compositions and methods of the present invention are directed totreatments for both existing estrogen- and androgen-mediated disordersand prevention thereof. Such disorders include, but are not limited to,prevention or treatment of osteoporosis, endometriosis, breast cancer,benign breast cancer, uterine cancer, ovarian cancer, polycystic ovariandisease, prostate cancer, benign prostatic hyperplasia (BPH), reductionof cardiac diseases, acne, seborrhea, alopecia, hirsutism, male patternbaldness, and infertility.

An embodiment of the therapeutic compound according to the invention isan antiestrogen compound having the structural formula, in theaddress/message construct described below:

a) an address unit having the structure:

wherein:

R¹ is H, CH₃, CH₂CH₃, OH, OCH₃, OCH₂CH₃, C₁-C₆ alkyl, CH═CH₂, CH═CHCH₃,CH₂-aryl;

R² is H, CH₃, COCH₃, CO(CH₂)_(n)CH₃, CO-aryl, alkyl, cycloalkyl (ether),ester, —COCH₃;

R³ is CH₃, CH₂CH₃, aryl, heteroaryl, alkyl C₁-C₆, alkyl (C₁-C₆) amides,alkyl (C₁-C₆) sulfide, alkyl (C₁-C₆) sulfone, alkyl (C₁-C₆) sulfoxide;

R⁹ is H, OH, NH₂; and, attached to the 17α-position of the address unit,

b) a message unit having the structure:

wherein:

R⁴ is H, alkyl (C₁-C₄);

R⁵ is aryl, heteroaryl, fused aryl, —CO-aryl, CO-fused aryl,—CO-heteroaryl, —CO-fused heteroaryl, biaryl, CO-biaryl, ether-linkedaryls, ether-linked heteroaryls, amine-linked aryls, amine-linkedheteroaryls, aminoalkoxy arene hybrid, peptidyl hybrid, wherein anyaryl, heteroaryl, fused aryl, fused heteroaryl, biaryl, CO-biaryl,ether-linked aryls, ether-linked heteroaryls, amine-linked aryls,amine-linked heteroaryls, aminoalkoxy arene hybrid, and peptidyl hybridas used herein for groups exemplified in Table 1, rows 13-15, mayoptionally be substituted, independently, with H, CH₃, OH, OCH₃, OCF₃,NCH₃, NCOCH₃, aryl, CO₂CH₃, CONH₂, C₁-C₄ alkyl, (CF₂)_(n)F whereinn=1-4, Cl, Br, I, F, O(CH₂)_(n)H wherein n=1-4, NO₂, NH₂, NHCOR⁴, CO₂H,CO₂R⁴, CONHR⁴, amyl, thioether, SR⁶, S(O)R⁶, SO₂R⁶, SO₂NR⁶R⁷; wherein R⁴has the definition given above; wherein R⁶ is H, C₁-C₄ alkyl orperfluoroalkyl, aryl, heteroaryl, or optionally substituted allyl,arylmethyl, alkynyl, alkenyl; wherein R⁷ is H, C₁-C₄ alkyl orperfluoroalkyl, aryl, heteroaryl, optionally substituted allyl,arylmethyl, OR⁸ or NHR⁸; wherein R⁸ is H, C₁-C₆ alkyl or perfluoroalkyl,aryl, heteroaryl, optionally substituted allyl or arylmethyl, SO₂R⁶ orS(O)R⁶, wherein R⁶ has the definition given above; and

wherein R⁵ can be in either the E or Z configuration in relation to the17α-position of the address unit.

Examples of the combined structural formula for the antiestrogencompounds of the present invention that includes both the address andthe message units are as follows:

In another embodiment, the present invention is directed to antiandrogencompounds having the structural formula, in the address/messageconstruct described below:

a) an address unit having one of the following different structures:

wherein:

R¹⁰ is H, CH₃;

R¹¹ is H, C₁-C₄ alkyl;

R¹² is O, (H, OH);

R¹³ is H, OH, Cl, Br, I, CH₃;

R¹⁴ is H, C₁-C₄ alkyl;

R¹⁵ is O, (H, OH);

R¹⁶ is O, NH;

R¹⁷ through R¹⁸ each independently is H, CH₃; and, attached to the17α-position of the address unit, and

b) a message unit having the structure:

wherein:

R⁴ is H, alkyl (C₁-C₄);

R⁵ is aryl, heteroaryl, fused aryl, —CO-aryl, CO-fused aryl,—CO-heteroaryl, —CO-fused heteroaryl, biaryl, CO-biaryl, ether-linkedaryls, ether-linked heteroaryls, amine-linked aryls, amine-linkedheteroaryls, wherein any aryl, heteroaryl, fused aryl, fused heteroaryl,biaryl, CO-biaryl, ether-linked aryls, ether-linked heteroaryls,amine-linked aryls, and amine-linked heteroaryls may optionally besubstituted, independently, with H, CH₃, OH, OCH₃, OCF₃, NCH₃, NCOCH₃,aryl, CO₂CH₃, CONH₂, C₁-C₄ alkyl, (CF₂)_(n)F wherein n=1-4, Cl, Br, I,F, O(CH₂)_(n)H wherein n=1-4, NO₂, NH₂, NHCOR⁴, CO₂H, CO₂R⁴, CONHR⁴,amyl, thioether, SR⁶, S(O)R⁶, SO₂R⁶, SO₂NR⁶R⁷; wherein R⁴ has thedefinition given above; wherein R⁶ is H, C₁-C₄ alkyl or perfluoroalkyl,aryl, heteroaryl, or optionally substituted allyl, arylmethyl, alkynyl,alkenyl; wherein R⁷ is H, C₁-C₄ alkyl or perfluoroalkyl, aryl,heteroaryl, optionally substituted allyl, arylmethyl, OR⁸ or NHR⁸;wherein R⁸ is H, C₁-C₆ alkyl or perfluoroalkyl, aryl, heteroaryl,optionally substituted allyl or arylmethyl, SO₂R⁶ or S(O)R⁶, wherein R⁶has the definition given above; and

wherein R⁵ can be in either the E or Z configuration in relation to the17α-position of the address unit.

Exemplary antiandrogen compounds containing both the address and themessage units are as follows:

Exemplary R⁵ groups of the present invention are as follows: TABLE 1EXEMPLARY R⁵ GROUPS

(o/m/p) n = 2-6 R = alkyl or cycloalkyl (C₄-C₈)

(o/m/p) amide bond L or D n = 1-4 R = alkyl or cycloalkyl (C₄-C₈)

(o/m/p) amide bond L or D n = 0-2 m = 0-3 R = alkyl or cycloalkyl(C₄-C₈)

The above exemplary structures can be substituted at the indicatedpositions with substituents as described above. Any aryl and heteroarylgroups can be substituted with one to five substituent groups,preferably one to three substituent groups. These substituent groups mayinclude, independently, H, CH₃, OH, OCH₃, OCF₃, NCH₃, NCOCH₃, aryl,CO₂CH₃, CONH₂, C₁-C₄ alkyl, (CF₂)_(n)F wherein n=1-4, Cl, Br, I, F,O(CH₂)_(n)H wherein n=1-4, NO₂, NH₂, NHCOR⁴, CO₂H, CO₂R⁴, CONHR⁴, amyl,thioether, SR⁶, S(O)R⁶, SO₂R⁶, SO₂NR⁶R⁷; wherein R⁴ has the definitiongiven above; wherein R⁶ is H, C₁-C₄ alkyl or perfluoroalkyl, aryl,heteroaryl, or optionally substituted allyl, arylmethyl, alkynyl,alkenyl; wherein R⁷ is H, C₁-C₄ alkyl or perfluoroalkyl, aryl,heteroaryl, optionally substituted allyl, arylmethyl, OR⁸ or NHR⁸;wherein R⁸ is H, C₁-C₆ alkyl or perfluoroalkyl, aryl, heteroaryl,optionally substituted allyl or arylmethyl, SO₂R⁶ or S(O)R⁶, wherein R⁶has the definition given above; and wherein R⁵ can be in either the E orZ configuration.

Any aryl and heteroaryl groups with any combinations thereof for thecompounds of the present invention can be substituted as elsewheredescribed, with one to five substituent groups. In a preferredembodiment, any aryl and heteroaryl groups with any combinations thereofcan be substituted as elsewhere described with one to three substituentgroups, where the preferred substituent positions are indicatedelsewhere herein.

These compounds are capable of effectively binding to the estrogen orthe androgen receptor, accordingly, to inhibit or modulate the actionsof either estrogens or androgens.

In another embodiment, the present invention is directed to atherapeutic composition for prophylaxis or treatment of ahormone-responsive disorder containing the antiestrogenic andantiandrogenic compounds described above. The therapeutic composition iscontained in a pharmaceutically acceptable inert carrier substance thatis formulated for oral, topical, intravenous, intramuscular,subcutaneous, intra-vaginal, suppository or parental administration.

In another embodiment, the present invention is directed to a method oftreating a patient suffering from or believed to be at risk of sufferingfrom a hormone-responsive disorder by administering to the patient aneffective amount of any of the therapeutic compositions described abovefor preventing or treating hormone-responsive disorders.

In a further embodiment, the therapeutic compositions of the presentinvention comprising the antiestrogen/antiandrogen compounds can beadministered, if a low dosage is preferred, in a dosage of about 0.1μg/kg (body weight) per day to 10 μg/kg/day, preferably 0.5 μg/kg/day to5 μg/kg/day, and preferably 1 μg to 100 μg for local administration. Anexemplary preferred high dosage amount may be in the range of about 0.10mg/kg/day to about 40 mg/kg/day, more preferably of about 0.50 mg/kg/dayto about 20 mg/kg/day, and more preferably of about 1.0 mg/kg/day toabout 10 mg/kg/day. Optimal dosage and modes of administration canreadily be determined by conventional protocols. The amount ofadministration is also dependent on the disease-state, on the patientbeing treated, the patient's body weight and the type of administration.

In a further embodiment, the present invention is directed to a kitcomprising a therapeutic composition as described above and instructionsfor use thereof.

In a particular embodiment, the present invention is directed to amethod for the prophylaxis or treatment of prostate disorders in apatient by administering an antiandrogenic compound described herein inan effective amount. While not being bound by any theory, it is believedthat in particular, the antiandrogenic compounds of the invention changethe structural conformation in the helix-12 of the androgen receptor toinhibit transcriptional response.

In another embodiment, the present invention is directed to an articleof manufacture comprising a packaging material and a therapeuticcomposition of the present invention contained within the packagingmaterial. The therapeutic composition is therapeutically effective forprophylactic or treatment of hormone-responsive disorders. The packingmaterial also comprises a label with instructions for use, whichindicates that the therapeutic composition can be used for phrophylaxisor treatment of hormone-responsive disorders.

BRIEF DESCRIPTION OF THE FIGURES

Other features and advantages of the invention will be apparent from thefollowing description of the preferred embodiments thereof and from theclaims, taken in conjunction with the accompanying drawings, in which:

FIG. 1 depicts the synthesis of the estradiol analogs according to theinvention by coupling the 3-phenolic group of 17α-ethynyl estradiol tothe carboxy polystyrene resin. The reagents and conditions used were asfollows:

a—Jones reagent (H₂Cr₂O₄, H₂SO₄, acetone);

b—n-BuLi, TMEDA, cyclohexane, 50° C.;

c—Dry ice, THF;

d—17α-Ethynyl estradiol, DCC, DMAP, CH₂Cl₂;

e—HSnBu₃, Et₃B, THF, 50-60° C.;

f—17α-Ethynyl estradiol, HSnBu₃, Et₃B, THF, 50-60° C.;

g—DCC, DMAP, CH₂Cl₂;

h—R-Aryl-X, Pd(PPh₃)₄, BHT, toluene, N₂, reflux;

i—5 N-NaOH in CH₃O H-Dioxane (1:3);

j—5%-CH₃COOH;

k—10%-NaHCO₃;

FIG. 2 depicts the synthesis of an exemplary address unit;

FIG. 3 depicts the synthesis of an exemplary message unit;

FIG. 4 depicts the synthesis of an address-message combination;

FIG. 5 depicts the E and Z isomers of 3-(trifluoromethyl)phenylvinylestradiol;

FIG. 6 depicts the exemplary composite of both the address and messageunits;

FIG. 7 depicts prior art antihormones that incorporate functional groupsat the 11β- or 7α-position of the steroid nucleus;

FIG. 8 depicts exemplary steroid nucleus (address component) and thenonsteroidal antagonist pharmacophore (message component);

FIG. 9 depicts prior art nonsteroidal ligands with antiandrogen messagecomponent (Helix-12 modulators);

FIG. 10 depicts the synthesis of message components using a modifiedcombination of organotin chemistry and palladium-catalyzed couplingreactions;

FIG. 11 a-11 c are graphs depicting the results of proliferation assaysof MCF-7 cells with (ortho, meta, or para)3-(trifluoromethyl)phenylvinyl estradiol;

FIG. 12 is a graph depicting the results of a three-day immature femalerat uterotrophic growth assay with (ortho, meta, or para)3-(trifluoromethyl)phenylvinyl estradiol;

FIG. 13 is a graph depicting the results of the estrogenicity of17α-(ortho, meta, or para) 3-(trifluoromethyl)phenylvinyl estradiols inthe immature female rat; and

FIG. 14 is a graph depicting the results of an antiestrogen assay of17α-(ortho, meta, or para) 3-(trifluoromethyl)phenylvinyl estradiols inthe immature female rat.

DETAILED DESCRIPTION OF THE INVENTION

Definition of Terms

The term “alkyl” used herein refers to a branched or unbranchedsaturated hydrocarbon group of 1 to 24 carbon atoms, such as methyl,ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, octyl, decyl,tetradecyl, hexadecyl, eicosyl, tetracosyl and the like. Preferred alkylgroups herein contain 1 to 12 carbon atoms. The term “lower alkyl”intends an alkyl group of one to six carbon atoms, preferably one tofour carbon atoms. The term “cycloalkyl” intends a cyclic alkyl group,typically of 3 to 6 carbon atoms, more preferably 4 to 5 carbon atoms.The term “cyclooxyalkyl” intends a cyclic alkyl group containing asingle ether linkage, again, typically containing 3 to 6 carbon atoms,more preferably 4 to 5 carbon atoms.

The term “aryl” as used herein refers to a monocyclic aromatic speciesof 5 to 7 carbon atoms, and is typically phenyl. Optionally, thesegroups are substituted with one to five, more preferably one to three,lower alkyl, lower flouroalkyl, lower alkoxy, halo, nitro, amino, amide,carboxy, thioether, sulfide, sulfoxide, sulfamino, and/or sulfamidesubstituents. The aryl group may also comprise of di-, tri-, hexa-,penta-substituted phenyl with all positional (ortho, meta, para)variations. The term “lower flouroalkyl” intends an alkyl group of oneto six carbon atoms, preferably one to four carbon atoms. The term“lower alkoxy” intends an alkoxy group with one to six carbon atoms,preferably one to four carbon atoms. The term “carboxy aryl” as usedherein refers to a carboxy group attached to the aryl group.

The term “halo” or “halogen” refers to fluoro, chloro, bromo or iodo,and usually relates to halo substitution for a hydrogen atom in anorganic compound.

The term “optional” or “optionally” means that the subsequentlydescribed event or circumstance may or may not occur, and that thedescription includes instances where said event or circumstance occursand instances where it does not.

The term “heteroaryl” as used herein refers to monocyclic aromaticspecies of three to seven carbon atoms, and is preferably one to sixcarbon atoms, and is more preferably one to five carbon atoms, and istypically phenyl. In particular, the heteroaryl comprises, for example,oxazole, thiazole, isoxazole, where these heteroaryls have nitrogen,oxygen, or sulfur atoms in the monocyclic ring. Optionally, these groupsare substituted with one to five, more preferably one to three, loweralkyl, lower flouroalkyl, lower alkoxy, halo, nitro, amino, amide,carboxy, thioether, sulfide, sulfoxide, sulfamino, and/or sulfamidesubstituents. The aryl group may also comprise of di-, tri-, hexa-,penta-substituted phenyl with all positional (ortho, meta, para)variations. The term “carboxy-heteroaryl” as used herein refers to acarboxy group attached to a heteroaryl group.

The term “fused aryl” as used herein refers to bicyclic aromatic speciesof three to seven carbon atoms, and is typically phenyl. In particular,the fused aryl may comprise of naphthyl, benzothienyl, or benzofuryl.Optionally, these groups are substituted with one to five, morepreferably one to three, lower alkyl, lower flouroalkyl, lower alkoxy,halo, nitro, amino, amide, carboxy, thioether, sulfide, sulfoxide,sulfamino, and/or sulfamide substituents. The aryl group may alsocomprise of di-, tri-, hexa-, penta-substituted phenyl with allpositional (ortho, meta, para) variations. The term “carboxy-fused aryl”as used herein refers to a carboxy group attached to a fused-aryl group.

The term “biaryl” as used herein refers to two monocyclic aromaticspecies of four to seven carbon atoms, and is typically differentconfigurations of a combination of a phenyl and a heteroaryl.Optionally, these groups are substituted with one to five, morepreferably one to three, lower alkyl, lower flouroalkyl, lower alkoxy,halo, nitro, amino, amide, carboxy, thioether, sulfide, sulfoxide,sulfamino, and/or sulfamide substituents. The aryl group may alsocomprise of di-, tri-, hexa-, penta-substituted phenyl with allpositional (ortho, meta, para) variations. The term “carboxy-biaryl” asused herein refers to a biaryl attached to a carboxy group.

The terms “ether-linked aryls” and “ether-linked heteroaryls” as usedherein refer to two aryls/heteroaryls as defined above that are linkedby an ether group. Optionally, these groups are substituted with one tofive, more preferably one to three, lower alkyl, lower flouroalkyl,lower alkoxy, halo, nitro, amino, amide, carboxy, thioether, sulfide,sulfoxide, sulfamino, and/or sulfamide substituents. The aryl group mayalso comprise of di-, tri-, hexa-, penta-substituted phenyl with allpositional (ortho, meta, para) variations.

The terms “amine-linked aryls” and “amine-linked heteroaryls” as usedherein refer to two aryls/heteroaryls as defined above that are linkedby an amine group. The terms aminoalkoxyl arene hybrids and peptidylhybrids as used herein are referred to the groups exemplified inTable 1. Optionally, these groups are substituted with one to five, morepreferably one to three, lower alkyl, lower flouroalkyl, lower alkoxy,halo, nitro, amino, amide, carboxy, thioether, sulfide, sulfoxide,sulfamino, and/or sulfamide substituents. Aryl group may also compriseof di-, tri-, hexa-, penta-substituted phenyl with all positional(ortho, meta, para) variations.

The term “effective amount” as used herein means a nontoxic butsufficient amount of a compound to provide the desired effect. The exactamount required will vary from patient to patient, depending on thespecies, age, and general condition of the patient, the severity of thecondition being treated, and the particular compound and its mode ofadministration. Thus, it is not possible to specify an exact “effectiveamount.” However, an appropriate effective amount may be determined byone of ordinary skill in the art using only routine experimentation.

The term “pharmaceutically acceptable” as used herein means a materialwhich is not biologically or otherwise undesirable, i.e., the materialmay be administered to a patient along with the selected compoundwithout causing any undesirable biological effects or interacting in adeleterious manner with any of the other components of thepharmaceutical composition in which it is contained.

The present invention comprises the design, synthesis and development ofa new class of chemotherapeutic agents for the treatment ofhormone-responsive disorders. In the new class of chemotherapeuticagents, two components—a message subunit or pharmacophore, present inthe nonsteroidal antagonists (e.g., antiandrogens, antiestrogens) andthe address subunit found in the steroidal agonists (e.g., androgens,estrogens)—are combined into a single composite entity. In particular,specific compounds in this new class of chemotherapeutic agents targetthe estrogen and/or the androgen receptors. The general formula for theagents of the invention was determined based on the discovery that theinteraction between androgen/estrogen with the receptor involves a twostep process. There is an initial association of the hormone (addresscomponent) with a specific part of the receptor, called the hormonebinding domain, followed by the induction of a conformational change inthe receptor (message component) that generates the observed biologicalresponse.

Accordingly, the present invention incorporates the “address-message”concept to generate, for example, prostate cancer tissue affinity,selectivity, and efficacy, and employs transition metalcatalysts/reagents to prepare the novel therapeutic compounds. As anembodiment, the present invention uses modified palladium catalysts forcarbon-carbon (Stille, Suzuki reactions) and carbon-nitrogen/oxygen(Buchwald, Hartwig) coupling reactions. As another embodiment of thepresent invention, the use of 1D/2D-NMR (Nuclear Magnetic Resonance) andthe molecular modeling in the evaluation of the conformational analysisof the target compounds provides the capability for biological andstructural data.

The novel therapeutic compounds constitute a structurally unique classof steroidal derivatives, e.g., derivatives of, for example,17α-(substituted)phenylvinyl-17β-estradiols as estrogens andantiestrogens, and corresponding (nor)testosterones anddihydro-derivatives. In particular, identification of the most potentand selective antagonists for prophylaxis and treatment provides for amore effective treatment of hormone-responsive disorders and therebyprolong the disease-free interval. The present invention provides for amore potent and effective agent which increases the initial responsecoupled with a slower progression to hormone independence. Additionally,the therapeutic compound of the present invention targets specificallyand more selectively thereby reducing the incidence and/or severity ofthe side effects of anti-estrogen or anti-androgen therapy.

EXAMPLES

The following examples are presented to illustrate the advantages of thepresent invention and to assist one of ordinary skill in making andusing the same. These examples are not intended in any way otherwise tolimit the scope of the disclosure.

Preferred antiestrogens/antiandrogens for the prevention or treatment ofits corresponding hormone-related disorder acting to inhibitestrogen/androgen action may be prepared accordingly as follows:

Example I Synthesis and Evaluation of Steroidal Antistrogens at the17α-Position of Estradiol

Solid Phase Synthesis of 17α-substitued Phenylvinyl Estradiols:

Materials

Reagents and solvents were obtained from commercial sources (Aldrich andSigma) and were used without further purification. Wang resins andcarboxylated polystyrene resins were obtained from Novabiochem. Theloading capacities of the resins, 0.75 mmol g⁻¹ for the Wang resin and2.47 mmol g⁻¹ for the polystyrene resin, were determined by themanufacturer.

General Methods

A specially designed flask which had a glass frit, through which thereaction mixture could be filtered by applying pressure, was used forthe solid phase synthesis. Purifications for the intermediates were doneby rinsing resins three times with the following solvents: CH₂Cl₂, THF,DMF, MeOH, CH₂Cl₂. The cleaved products were purified on a silica gelcolumn chromatography using the appropriate solvents and werecharacterized by melting point, NMR, IR and electrical analysis. Meltingpoints were determined in open capillary on an Electrothermal MeltingPoint Apparatus and were uncorrected. IR spectra were recorded on aPerkin-Elmer Model 1600 FT-IR spectrometer. ¹H and ¹³C NMR spectra wereobtained with a Varian XL-300 NMR spectrometer at 300 MHz in CDCl3,acetone-d₆, or DMSO-d₆ as a solvent. Elemental analyses were performedby Atlantic Microlab, Inc. (Norcross, Ga.). As on-resin reactionmonitoring methods, color tests and FT-IR methods were used. Bomoscresolgreen (0.5% in ethanol, pH=8) was used to assay for free carboxylicacids.¹⁸ The color of the stock solution was dark blue and changed toyellow in the presence of free carboxy groups. Antimony (III) chloridesolution (25% in CCl₄) was also used to determine whether the steroid(17α-ethynyl estradiol) was coupled to the resin and a positive testresult for the presence of estradiol was indicated by the color purple(Carr, 1926; Blatz, 1972; Jork, 1990). In addition, a spectro-scopicmethod (FT-IR) was facilitated to detect chromophore change by reaction.

Preparation of the Carboxylated Resin

(Method A). The Wang resins (1 g, 0.75 mmol) were swelled in the CH₂Cl₂overnight and rinsed twice with THF, CH₃OH, CH₂Cl₂ and acetone. Acetone(5 mL) was added to the swelled resins. To the slurry was added 1 mL ofJones reagent (Bowden, 1946) in a dropwise manner. The mixture wasallowed to stand at room temperature for 24 h. The resin mixture wasrinsed twice with water-acetone (1:1), CH₃OH, DMF, DMSO and CH₂Cl₂ anddried in vacuo. The loading capacity after the carboxylation reactionwas 0.4-0.6 mmol g⁻¹, which was determined with the coupling of17α-ethynyl estradiol to the resin. The aliquot of the resins wascharacterized by FT-IR. FT-IR (KBr) v: 3000-3500 (OH, broad), 1690 (C═O,broad), 1603, 1492, 1452 (aromatic ring), 1279 (C—O).

(Method B). The carboxylation of a polystyrene resin was accomplishedusing the method described by Farrall et al. (Farrall, 1976). FT-IR(KBr) v: 3420 (OH, broad), 1630 (C═O, broad), 1200-1400 (C—O, broad).Loading capacity: 1.5-1.9 mmol g⁻¹.

Coupling 17α-Ethynyl Estradiol to the Resins

The carboxylated Wang resin (2.3 g) or polystyrene resin (2.5 g) wasplaced in the reactor equipped with a magnetic stirrer. The resin wasswelled in the ch₂cl₂ for 5 h and washed sequentially with THF, DMF,CH₃OH, THF and CH₂CL₂. To the resin was added 0.23 g (1.1 mmol) ofdicyclohexylcarbodiimide (DDC) and 5 ml of CH₂CL₂ and the mixture wasmildly stirred for 10 min. To the slurry was added 0.75 g (2.6 mmol) of17α-ethynyl estradiol dissolved in 10 ml of CH₂CL₂-DMF (9:1) solvent andcatalytic amount of 4-dimethylaminopyridine (DMAP). The reaction mixturewas stirred for 5 min and then allowed to stand at room temperature for24 h. The resin was washed three times with CH₂CL₂ CH₃OH, IPA (60° C.),THF and DMF (60° C.) (Morales, 1998). The rinsed resin was dried undervacuum for 5 h. The actual loading of the resin was determined byquantitative measurement of the material by cleavage from known weightof resin using 5 N-NaOH in CH₃O H-dioxane (1:3). The resin-boundsteroids were characterized by FT-IR and the cleaved compounds by ¹H and¹³C NMR before proceeding to the next step. The loading capacity of eachresin was shown in Method A and B; FT-IR (KBr) v; 3437 (17β-OH), 3301(17α-C≡C—H), 1735 (C═O), 1607, 1493, 1452 (aromatic ring), 1216(C—O).

Hydrostannylation

(Method A). The 17α-ethynyl estradiol coupled to the resin (0.49 g, 0.57mmol g⁻¹) was placed in a dry 25 mL reaction flask equipped with areflux condenser and a magnetic stirrer and was swelled in THF for 1 h.To the slurry in the dry THF were treated triethylborane (0.7 mL) andtributyltin hydride (1 mL) (Nozaki, 1989). The mixture was allowed tostand at 60-70° C. for 48 h under a nitrogen atmosphere. The reactionmixture was washed three times each with CH₂Cl₂, CH₃OH, DMF, CH₂Cl₂ andethyl acetate and the resultant resin was dried in vacuo. An aliquot ofthe resins was cleaved with 5 N NaOH in CH₃OH—CH₂Cl₂ (1:2) to afford amixture of E- and Z-isomers. The mixture was separated by chromatographyon the silica gel to give a 23% (0.13 mmol g⁻¹) yield of products,consisting of 21% (0.12 mmol g⁻¹) of the E-isomer and 2% (0.01 mmol g⁻¹)of the Z-isomer. R_(f) (Z-isomer=0.58 (hexane-ethyl acetate, 4:1); R_(f)(E-isomer)=0.44 (hexane-ethyl acetate, 4:1); Amorphous; ¹H NMR (CDCl₃,300 MHz, δ), 0.88 (s, 3H, C₁₈-methyl-H), 1.2-2.4 (m, steroid envelopeand tributyl-stannyl-H), 2.7-2.9 (m, 2H, C₆-H), 6.06 (d, 1H, J=19.4 Hz,C₂₁ vinyl-H), 6.22 (d, 1H, J=19.4 Hz, C₂₀ vinyl-H), 6.79 (d, 1H, J=2.4Hz, C₄-H), 6.84 (dd, 1H, J=2.6, 8.4 Hz, C₂-H), 7.28 (d, 1H, J=8.8 Hz,C₁-H); ¹³C NMR (CDCl₃), 9.6 (C₂₂, 4C), 13.7 (C₂₄, 4C), 14.2 (C₁₈), 23.4(C₁₅), 26.4 (C₁₁), 27.3 (C₂₅, 4C), 27.4 (C₇), 29.2 (C₂₃, 4C), 29.6 (C₆),32.4 (C₁₂), 35.9 (C₁₆), 39.4 (C₈), 43.8 (C₉), 46.7 (C₁₃), 49.0(C₁₄),85.6 (C₁₇), 112.6 (C₂), 115.2 (C₄), 124.6 (C₂₁), 126.5 (C₁), 132.7(C₁₀), 138.3 (C₅), 152.4 (C₂₀), 153.3 (C₃), FT-IR (KBr) v: 3445 (17β-OH,broad, 1719 (C═O), 1653 (C═C), 1607, 1493, 1451 (aromatic ring), 1217(C—O).

(Method B). The 17α-ethynyl estradiol (3 g, 10 mmol) was dissolved inTHF and treated with triethylborane (2 mL, 17 mmol) and tributyltinhydride (3 g, 11 mmol). The mixture was stirred with a magnetic stirrerat 60° C. for 16 h. The crude mixture (7.73 g) was evaporated todryness, redissolved in the CH₂Cl₂, and transferred to the swelled resin(5 g) in CH₂Cl₂ in the presence of DCC. A catalytic amount of DMAP wasadded to the mixture, which was allowed to stand for 24 h. The resultantfunctionalized resin was treated as previously described. The totalloading for both E- and Z-isomers was 0.59 mmol g−1 with 0.56 mmol g⁻¹of E-isomer and 0.03 mmol g⁻¹ of Z-isomer, however, by the dry weightdifference between pre- and post-reaction, the loading for both E- andZ-isomers was 1.55 mmol g⁻¹.

Electrophilic Destannylation on the Resin

The Stille reaction was used to couple the anchored E- andZ-stannylvinyl estradiol to aryl halides. The resin was added to thereaction flask, swelled in the CH₂Cl₂, subsequently treated with 10 mLof anhydrous toulene. To the resultant slurry was added a 3-4 foldexcess of the functionalized aryl halide, 1-2 crystals of3.5-di-t-butyl-4-hydroxytoulene (BHT), and Pd (PPh₃)₄ (Bowden, 1946;Farrall, 1976). The reaction was allowed to proceed at 90-100° C. for 24h. After cooling, the resin was washed as previously described, dried invacuo and weighed.

Cleavage

The resin was swelled in CH₂Cl₂ (10 mL) containing 3 mL of 5 N-NaOH inCH3OH-Dioxane (1:3) and stirred for 1 h. This cleavage step was repeatedthree times. Most of the product was collected from the first attempt, asmall amount by second hydrolysis, and almost none from the third trial.The fractions were combined, evaporated to dryness, and partitionedbetween ethyl acetate and water. Acetic acid (1 mL, 5%) was added. Theorganic phase was washed with 10% aqueous NaHCO₃ to remove the residualacetic acid, dried over MgSO₄, filtered and evaporated to dryness. Thecrude product was purified by silica gel column chromatography or byrecrystallization from the appropriate solvent.

17α-20E-21-(2-Trifluoromethylphenyl)-19-norpregna-1,3,5(10),20-tetraene-3,17β-diol (17α-E-(2-trifluoromethylphenyl)-vinyl estradiol)(4a). Yield=38%; R_(t)=0.19 (hexane-ethyl acetate, 4:1); mp 224-225° C.;¹H NMR (300 MHz, Acetone-d₆, δ) 1.02 (s, 3H, C₁₈ methyl-H), 1.2-2.4 (m,steroid envelope), 2.7-2.9 (m, 2H, C₆-H), 3.98(s, 1H, 17β hydroxyl-H),6.53 (d, 1H, J=2.3 Hz, C₄-H), 6.58 (dd, 1H, J=2.6, 8.5 Hz, C₂-H), 6.64(d, 1H, J=15.7 Hz, C₂₀ vinyl-H), 7.0 (dd, 1H, J=2.5, 15.8 Hz, C₂₁vinyl-H), 7.07 (d, 1H, J=8.7 Hz, C₁-H), 7.42 (t, 1H, J=7.8 Hz, C₂₆-H),7.60 (t, 1H, J=7.3 Hz, C₂₅-H), 7.69 (d, 1H, J=7.8 Hz, C₂₇-H), 7.81 (d,1H, J=8.3 Hz, C₂₄-H), 7.98 (s, C₃ hydroxy-H); 13C NMR (75.4 MHz,Acetone-d₆, δ) 14.7 (C₁₈), 24.1 (C₁₅) 27.2 (C₁₁), 28.3 (C₇), (C₆), 33.4(C₁₂), 37.5 (C₁₆), 40.7 (C₈), 44.6 (C₉), 48.4 (C₁₃), 50.0 (C₁₄), 84.3(C₁₇), 113.5 (C₂), 115.9 (C₄), 123.4 (C₂₁), 125.6 (q, J=273.2 Hz,C₂₈:CF₃), 126.4 (q, J=5.8 Hz, C₂₄), 127.0 (C₁), 127.4 (q, J=29.4 Hz,C₂₃), 127.8 (C₂₆), 128.6(C₂₇), 132.0 (C₂₅), 133.2 (C₁₀), 137.9 (C₂₂),139.1 (C₅), 142.4 (C₂₀), 155.9 (C₃); Anal. Calcd for C₂₇H₂₉O₂F₃: C,73.30; H, 6.56. Found: C, 73.04; H, 6.68.

17α-20E-21-(3-Trifluoromethylphenyl)-19-norpregna-1,3,5(10),20-tetraene-3,17β-diol (17α-E-(3-trifluoro methylphenyl)-vinylestradiol) (5a). Yield=33%; R_(f) (E-isomer)=0.19 (hexane-ethyl acetate,4:1); mp 244-246° C.; ¹H NMR (300 MHz, Acetone-d₆, δ), 1.01 (s, 3H,C₁₈-methyl), 1.2-2.4 (m, steroid envelope), 2.7-2.9 (m, 2H, C₆-H), 3.98(s, 1H, 17β, hydroxyl-H), 6.53 (d, 1H, J=2.6 Hz, C₄-H), 6.58 (dd, 1H,J=2.6, 8.3 Hz, C₂-H), 6.74 (d, 1H, J=16 Hz, C₂₁ vinyl-H), 6.84 (d, 1H,J=16 Hz, C₂₀ vinyl-H), 7.06 (d, 1H, J=8.3 Hz, C₁-H), 7.54-7.56 (m, 2H,C₂₅, C₂₇-H), 7.75-7.79 (m, 2H, C₂₃, C₂₆-H), 7.93 (s, C₃-hydroxy-H) ; ¹³CNMR (75.4 MHz, Acetone-d₆, δ), 14.7 (C₁₈), 24.1 (C₁₅), 27.3 (C₁₁), 28.3(C₇), (C₆), 33.5 (C₁₂), 37.5 (C₁₆), 40.7 (C₈), 44.6 (C₉), 48.4 (C₁₃),50.1 (C₁₄), 84.2 (C₁₇), 113.5 (C₂), 115.9 (C₄), 123.6 (q, J=5.6 Hz,C₂₅), 124.1 (q, J=3.7 Hz, C₂₃), 125.4 (q, J=271 Hz, C₂₈:CF₃), 126.0(C₂₆), 127.0 (C₁), 130.2 (C₂₁), 130.7 (C₂₇), 131.2 (q, J=32 Hz, C₂₄),132.0 (C₁₀), 138.4 (C₅), 139.7 (C₂₀), 139.9 (C₂₂), 155.9 (C₃); Anal.Calcd for C₂₇H₂₉O₂F₃: C, 73.30; H, 6.56. Found: C, 73.42; H, 6.68.

17α-20E-21-(4-Trifluoromethylphenyl)-19-norpregna-1,3,5(10),20-tetraene-3, 17β-diol (17α-E-(4-trifluoro methylphenyl)-vinylestradiol) (6a). Yield=49%; R_(f)=0.15 (hexane-ethyl acetate, 4:1); mp215-217° C.; ¹H NMR (Acetone-d₆, 300 MHz, δ), 1.02 (s, 3H, C₁₈methyl-H), 1.2-2.4 (m, steroid envelope), 2.7-2.9 (m, 2H, C₆-H), 3.90(s, 1H, 17β hydroxyl-H), 6.53 (d, 1H, J=2.6 Hz, C₄-H), 6.58 (dd, 1H,J=2.6, 8.4 Hz, C₂-H), 6.73 (d, 1H, J=16 Hz, C₂₁ vinyl-H), 6.85 (d, 1H,J=16 Hz, C₂₀ vinyl-H, 7.07 (d, 1H, J=8.3 Hz, C₁-H), 7.64 (d, 2H, J=8.7Hz, C₂₃, C₂₇-H), 7.70 (d, 2H, J=8.6 Hz, C₂₄, C₂₆-H), 8.0 (s,C₃-hydroxy-H); ¹³C NMR (75.4 MHz, Acetone-d₆, δ) 14.7 (C₁₈), 24.1 (C₁₅),27.3 (C₁₁), 28.3 (C₇), (C₆), 33.5 (C₁₂), 37.6 (C₁₆), 40.7 (C₈), 44.6(C₉), 48.5 (C₁₃), 50.2 (C₁₄), 84.2 (C₁₇), 113.5 (C₂), 115.9 (C₄), 125.4(q, J=270.6 Hz, C₂₈:CF₃), 126.0 (C₂₁), 126.2 (q, J=3.5 Hz, C₂₆), 126.2(q, J=3.5 Hz, C₂₄), 127.0 (C₁), 127.6 (C₂₃, C₂₇), 128.9 (q, J=32 Hz,C₂₅), 132.0 (C₁₀), 138.4 (C₅), 140.6 (C₂₀), 142.7 (C₂₂), 155.9 (C3);Anal. Calcd for C₂₇H₂₉O₂F₃: C, 73.30; H, 6.56. Found: C, 73.36; H, 6.79.

17α-20Z-21-(4-Trifluoromethylphenyl)-19-norpregna-1,3,5(10),20-tetraene-3,17β-diol (17α-Z-(4-trifluoro methylphenyl)-vinylestradiol) (6b). Yield=17%; R_(f)=0.29 (hexane-ethyl acetate, 4:1); ¹HNMR (300 MHz, Acetone-d₆, δ) 0.97 (s, 3H, C₁₈ methyl-H), 1.2-2.4 (m,steroid envelope), 2.7-2.9 (m, 2H, C₆-H), 3.89 (s, 1H, 17β hydroxyl-H),6.12 (d, 1H, J=12.9 Hz, C₂₁ vinyl-H), 6.48-6.62 (m, 3H, C₂, C₄, C₂₀vinyl-H), 7.11 (d, 1H, J=8.1 Hz, C₁-H), 7.59 (d, 2H, J=8.4 Hz, C₂₃,C₂₇-H), 7.80 (d, 2H, J=8.4 Hz, C₂₄, C₂₆-H), 7.95 (s, C₃ hydroxy-H).

17α-20E-21-(2-Methylphenyl)-19-norpregna-1,3,5(10),20-tetraene-3,17β-diol (17α-E-(2-methylphenyl)-vinyl estradiol) (7a).Yield=38%; R_(t)=0.18 (hexane-acetone, 4:1); mp 199-200° C.; ¹H NMR(Acetone-d₆, 300 MHz, δ), 1.01 (s, 3H, C₁₈ methyl-H), 1.2-2.4 (steroidenvelope), 2.34 (s, 3H, C₂₈ methyl-H), 2.7-2.9 (m, 2H, C₆-H), 3.84 (s,1H, 17β hydroxyl-H), 6.44 (d, 1H, J=16 Hz, C₂₁ vinyl-H), 6.52-6.63 (m,2H, C₂, C₄-H), 6.83 (d, 1H, J=16 Hz, C₂₀ vinyl-H), 7.07 (d, 1H, J=8.3Hz, C₁-H), 7.10-7.15 (m, 3H, C₂₄, C₂₅, C₂₆-H), 7.48 (d, 1H, J=6.8 Hz,C₂₇-H), 7.97 (s, C₃ hydroxy-H); ¹³C NMR (75.4 MHz, Acetone-d₆, δ) 14.7(C₁₈), 19.9 (C₂₈, methyl), 24.1 (C₁₅), 27.3 (C₁₁), 28.3 (C₇), (C₆), 33.5(C₁₂), 37.5 (C₁₆), 40.7 (C₈), 44.7 (C₉), 48.2 (C₁₃), 50.1 (C₁₄), 84.2(C₁₇), 113.5 (C₂), 115.9 (C₄), 125.4 (C₂₆), 126.5 (C₂₅), 126.9 (C₂₄),127.0 (C₁), 127.7 (C₂₁), 130.8 (C₂₇), 132.0 (C₁₀), 135.9 (C₂₀), 137.9(C₂₂), 138.4 (C₅), 138.8 (C₂₃), 155.9 (C₃); Anal. Calcd for C₂₇H₃₂O₂: C,83.51; H, 8.25. Found: C, 83.79; H, 8.65.

17α-20E-21-(3-Methylphenyl)-19-nonpregna-1,3,5(10), 20-tetraene-3,17β-diol (17α-E-(3-methylphenyl) -vinyl estradiol) (8a). Yield=75%;R_(t)=0.17 (hexane-acetone, 4:1); mp 204-205° C.; ¹H NMR (300 MHz,Acetone-d₆, δ), 1.00 (s, 3H, C₁₈ methyl-H), 1.2-2.4 (m, steroidenvelope), 2.31 (s, 3H, C₂₈ methyl-H), 2.7-2.9 (m, 2H, C₆-H), 3.74 (s,1H, 17β hydroxyl-H), 6.52-6.63 (m, 4H, C₄, C₂, C₂₁ vinyl, C₂₀ vinyl-H),7.03 (d, 1H, J=7.3 Hz, C₂₅-H), 7.07 (d, 1H, J=8.7 Hz, C₁-H), 7.16-7.31(m, 3H, J=7.4 Hz, C₂₃, C₂₆, C₂₇-H), 7.93 (s, 1H, C₃ hydroxy-H); ¹³C NMR(75.4 MHz, Acetone-d₆, δ) 14.8 (C₁₈), 21.4 (C₂₈; methyl), 24.1 (C₁₅),27.3 (C₁₁), 28.4 (C₇), (C₆), 33.5 (C₁₂), 37.4 (C₁₆), 40.8 (C₈), 44.7(C₉), 48.3 (C₁₃), 50.2 (C₁₄), 84.2 (C₁₇), 113.6 (C₂), 116.0 (C₄), 124.4(C₂₇), 127.0 (C₁), 127.7 (C₂₅), 127.8 (C₂₆), 128.5 (C₂₁), 129.2 (C₂₃),132.2 (C₁₀), 137.0 (C₂₀), 138.4 (C₅), 138.7 (C₂₂, C₂₄), 155.9 (C₃);Anal. Calcd for C₂₇H₃₂O₂: C, 83.51; H, 8.25. Found: C, 83.23; H, 8.42.

17α-20Z-21-(3-Methylphenyl)-19-norpregna-1,3,5(10),20-tetraene-3,17β-diol (17α-Z-(3-methylphenyl)-vinyl estradiol) (8b).Yield=54% (0.01 g); R_(t)=0.25 (hexane-acetone, 4:1); ¹H NMR (300 MHz,Acetone-d₆, δ) 0.95 (s, 3H, C₁₈ methyl-H), 1.2-2.4 (m, steroidenvelope), 2.31 (s, 3H, C₂₈ methyl-H), 2.7-2.9 (m, 2H, C₆-H), 3.27 (s,1H, 17β hydroxyl-H), 5.96 (d, 1H, J=13.1 Hz, C₂₁ vinyl-H, 6.44 (d, 1H,J=13.1 Hz, C₂₀ vinyl-H), 6.53 (d, 1H, J=2.6 Hz C₄-H), 6.60 (dd, 1H,J=2.6, 8.3 Hz, C₂-H), 7.03 (d, 1H, J=7.3 Hz, C₂₅-H), 7.11 (d, 1H, J=8.3Hz, C₁-H), 7.17 (t, 1H, J=7.6 Hz, C₂₆-H), 7.38-7.43 (m, 2H, C₂₃, C₂₇-H),7.95 (s, 1H, C₃ hydroxy-H); 13C NMR (75.4 MHz, Acetone-d₆, δ) 14.58(C₁₈), 21.42 (C₂₈: methyl). 23.85 (C₁₅), 27.40 (C₁₁), 28.30 (C₇), (C₆),32.97 (C₁₂), 38.4 (C₁₆), 40.9 (C₈), 44.7 (C₉), 48.8 (C₁₃), 50.1 (C₁₄),84.3 (C₁₇), 113.6 (C₂), 116.0 (C₄), 127.1 (C₁), 127.8 (C₂₇), 128.1(C₂₅), 128.3 (C₂₆), 129.7 (C₂₁), 131.4 (C₂₃), 132.0 (C₁₀), 137.1 (C₂₀),137.6 (C₂₄), 138.45 (C₅), 138.5 (C₂₂), 155.9 (C₃); Anal. Calcd forC₂₉H₃₆O₃: C, 80.55; H, 8.33. Found: C, 80.00; H, 8.41

17α-20E-21(4-Methoxyphenyl)-19-norpregna-1,3,5,(10),20-tetraene-3,17β-diol (17α-E-(4-methoxyphenyl)-vinyl estradiol) (9a).Yield=36%; R_(t)=0.23 (CHCl₃-CH₃OH, 99:1); ¹H NMR (300 MHz, Acetone-d₆,δ) 0.99 (s, 3H, C₁₈ methyl-H), 3.68 (s, 1H, 17β hydroxy-H), 3.78 (s, 3H,C₂₈:methoxy-H), 6.46 (d, 1H, J=16.1 Hz, C₂₁-H), 6.51-6.59 (m, 3H, C₂,C₄, C₂₀-H), 6.88 (d, 2H, J=8.8 Hz, C₂₄, C₂₆-H); 7.07 (d, 1H, J=8.3 Hz,C₁-H); 7.39 (d, 2H, J=8.8 Hz, C₂₃, C₂₇-H), 7.95 (s, 1H, C₃ hydroxy-H );¹³C NMR (75.4 MHz, Acetone-d₆, δ) 14.7 (C₁₈), 24.1 (C₁₅), 27.3 (C₁₁),28.3 (C₇), (C₆), 33.4 (C₁₂), 37.3 (C₁₆), 40.7 (C₈), 44.7 (C₉), 48.2(C₁₃), 50.0 (C₁₄), 55.5 (C₂₈:methoxy), 84.1 (C₁₇), 113.5 (C₂), 114.7(C₂₄, C₂₆), 115.9 (C₄), 127.0 (C₁), 127.0 (C₂₁), 128.3 (C₂₃, C₂₇), 131.4(C₂₂), 132.1 (C₁₀), 134.9 (C₂₀), 138.4 (C₅) 155.9 (C₃), 159.9 (C₂₅).

In the above procedures, the Solid Phase Synthesis methodology wasapplied using carboxylated resins to generate a series of novel ER-LBDligands, or estradiol derivatives. The purification steps weresimplified and simultaneously produced both the E- and Z-isomers. Yieldmay be improved by modifications in both the coupling and cleavage stepsfor a chemically more sensitive Z-isomer.

One of the key elements of the synthetic scheme was the selection of alinker that could be both formed and cleaved under mild conditions.17α-substituted estradiols were unstable under strongly acidicconditions such as those frequently used to release products from theresins. Therefore the resin of choice was carboxylated polystyrene whichcould be esterified under neutral conditions and ultimately cleaved withmild base. Compound 8a was prepared using the carboxylated resinobtained either by oxidation of a Wang resin using Jones reagent(Bowden, 1946) or by carboxylation of a polystyrene resin via lithiationwith n-butyl lithium (Farrall, 1976). The reactions for both methodswere easily monitored by the appearance of the 1700 cm⁻¹ absorption inthe FT-IR spectrum. The loading capacity of the carboxylated resins wasdetermined by coupling 17α-ethynyl estradiol onto the resins using DCCin the presence of catalytic amount of DMAP and measuring itssubsequently cleaved estradiol derivatives from the aliquot of theresins. The loading¹ of oxidized Wang resin was 0.4-0.6 mmol g⁻¹ andthat of carboxylated polystyrene was 1.5-1.9 mmol g⁻¹. Once the utilityof coupling through the ester linkage using carboxy polystyrene resinwas confirmed, the commercially available carboxy poolystyrene was usedfor the remainder of the work. The loading yield of the reaction usingthe resins with already known loading capacity (2.47 mmol g⁻¹) was 82%.The yield was determined by ‘cleave and characterize’ methods.¹ The loading capacities for the functionalized resins were expressed inmmol g⁻¹ and for the following steps were expressed in % or mmol g⁻¹.

As shown in FIG. 1, the synthesis of the analogs was initiated bycoupling the 3-phenolic group of 17α-ethynyl estradiol to the carboxypolystyrene resin. The steroids on the resins were confirmed by anantimony (III) chloride assay (Carr, 1926; Blatz, 1972; Jork, 1990). Dueto the absence of color change with bromocresol green, no freecarboxylic acid groups remained on the resin (Gordon, 1972). Theappearance of a peak at 3301 cm⁻¹ in the IR spectrum, corresponding tothe C-H stretch of the ethynyl group, also confirmed that the reactionand a shift of carbonyl absorption to higher frequency (from 1690-1734cm⁻¹) was also observed.

The subsequent hydrostannylation step incorporated either the use ofhydrostannylation of bound ethynyl estradiol (Method A) orhydrostannylation of ethynyl estradiol in solution phase synthesisfollowed by coupling to the resin (Method B). The resin-bound17α-ethynyl estradiol was hydrostannylated with tributyltin hydrideusing triethyl-borane as a radical initiator (Nozaki, 1989) to afford amixture of the 17α-E/Z-tri-n-butylstannylvinyl estradiol in 20-30% (0.12mmol g⁻¹ of E, 0.01 mmol g⁻¹ of Z) loading yields. Varying the reactionconditons, e.g. different solvents, temperatures, or reaction times, didnot improve the yields. Therefore, a direct coupling of17α-E/Z-tri-n-butylstannyl-vinyl estradiols was used to overcome the lowefficiency of this step. 17α-Ethynyl estradiol was hydrostannylated to60° C. and the crude mixture was directly transferred to the resinslurry in CH₂Cl₂. The mixture was treated with a 2-3 fold excess of DCCand a catalytic amount of DMAP was added. The loading yield for thecoupling reaction was 0.59 mmol g⁻¹ with a Z/E ratio=1:20. The lowloading yield was due to the use of the acetic acid for the protonationof phenoxide ion after cleavage, subjecting the products toprotiodestannylation and reducing the expected loading yield. Becausethe cleavage after hydrostannylation did not provide a precise loadingyield, the dry weight difference between pre-and post-reaction wassubsequently used to determine the loading yield. Using the dry weightdifference method, the yield for the hydrostannylation reaction was 1.55mmol g⁻¹ for both E- and Z-isomers. Because hydrostannylation on theresin did not afford satisfactory yields. Method B was the method ofchoice. The ratio of E and Z isomers is a function of the reactiontemperature, time and stoichiometric ratio of tributyltin hydride toalkyne. At 60° C. the reaction generated greater than 20:1 (E/Z) ratiobound to the solid phase. To increase the ratio of the Z-isomer,triethylborane was used as a radical initiator and the reaction was runat low temperature. The proportion of the Z-isomer (Z/E=1:10) wasincreased. However, the reaction required a longer time and the loadingyield for the hydrostannylation was slightly lower than at highertemperature (1.44 mmol g⁻¹ by the dry weight difference method) becauseof more unreacted 17α-ethynyl estradiol in the reaction mixture.

The resin-bound hydrostannnylated estradiol was subjected to the Stillecoupling reaction (Stille, 1985) using a variety of substituted arylhalides to generate the target compounds (see Table 2). As shown in FIG.1, Pd(PPh₃)₄ was used as the catalyst for the reaction and3,5-di-t-butyl-4-hydroxytoluene (BHT) was added as a scavenger. The useof Pd(PPh₃)₄ generated an insoluble by-product that caused coloration ofthe resin, however, it was easily removed by rinsing it through thebuilt-in filter (50-70 μm). After completion of all the reaction steps,the product was cleaved from the resin by saponification with 5 N NaOHdissolved in CH₃OH-Dioxane (1:3) TABLE 2

Compound R¹(ortho) R²(meta) R³(para) Yield (%) 4a:E CF₃ H H 38 Sa:E HCF₃ H 33 6a:E H H CF₃ 49 6b:Z H H CF₃ 17 7a:E CH₃ H H 33 Sa:E H CH₃ H 75Sb:Z H CH₃ H 54 9a:E H H OCH₃ 36

As shown in Table 2, the unoptimized yields of the Stille reactions onsolid phase ranged from 17-75%, comparable to those observed forsolution phase synthesis. Compounds 5a (para-trifluoromethylphenyl,E-isomer) and 5b (para-trifluoromethylphenyl, Z-isomer) were isolatedfrom the Stille reaction in a ratio of 98:2. Compound 7a(meta-methylphenyl, E-isomer) and 7b (meta-methylphenyl, Z-isomer) werealso obtained in a ratio of 96:4. Although the Z-tri-n-butylstannylvinyl estradiol was initially present on the resin, no Z-isomers ofcompounds 3a, 4a, 6a, or 8a were isolated from the Stille coupling,instead, 17α-vinyl estradiol, resulting from protiodestannylation wasrecovered as a side product. Because an excess of reagent was used todrive the reaction to completion, unreacted hydrostannylated17α-E/Z-(tri-n-butylstannyl)-vinyl estradiol was no detected after theStille reaction. It is possible that the Z-isomers either isomerized tothermodynamically more stable E-isomers under the conditions requiredfor the Stille reaction or underwent protiodestannylation. As previouslyobserved, the Z-isomer is much more susceptible to protiodestannylationthan the E-isomer and the appearance of the side product under eithersolid phase or solution phase synthesis was approximately the same.

The isolated product were characterized by standard spectroscopicmethods (FT-IR, ¹H and ¹³C NMR) and analytical methods. The data wereconsistent with the proposed structures. Stereochemical assignments forcompounds 5a and 5b were based on the C₂₀, C₂₁ olefinic proton couplingconstants for which E=16 Hz and Z-12.9 Hz, respectively. For compounds7a and 7b, the observed coupling constants were 18.2 Hz of the C₂₀E-vinyl proton and 13.1 Hz for the C₂₀ Z-vinyl proton. In ¹³C NMR, longrange couplings were observed for the compounds 3a-5a and 5b containingthe trifluoromethyl group. Coupling with strongly electronegativefluorine was found at the carbon directly attached to the fluorine(¹J_(C-F)) and one (²J_(C-F)) and two carbons distant (³J_(C-F)). Thecarbons appeared as quartets and the coupling constants wereapproximately ¹J_(C-F)=270 Hz. ²J_(C-F)=32 Hz. ³J_(C-F)=3-5 HZrespectively.

Variability of Ortho, Meta, Para-Substitutions

Ortho, meta, and para (trifluoromethyl)phenylvinyl estradiol isomerswere evaluated for estrogen receptor-ligand binding domain (ER-LBD)affinity. The properties of the aryl substituent and its position on thering (ortho/meta/para) affect receptor binding.

Trifluoromethyl group was introduced onto phenylvinyl estradiol eitherat the ortho, meta, or para positions. These compounds were examined fortheir ability to stimulate or inhibit estrogen responses in two assaysystems. The initial system evaluated the ability of the ligand tostimulate the proliferation of MCF-7 cells and as the results in FIG. 11indicate, the ortho-isomer produced a full agonist response comparableto that of estradiol. When the ligand was added to the cells in thepresence of 1 nM estradiol, there was neither an enhancement nor adiminution of the proliferative response. The meta- and para-isomersgave substantially different profiles. The meta-isomer demonstrated aweak proliferative effect at doses greater than 1 nM and antagonized theeffects of estradiol at the same doses. The para-isomer, however, didnot elicit a proliferative response until a 10 nM dose was employed anddecreases in the estradiol effects were observed below 1 nM. Therefore,the position of the trifluoromethyl group exerted a significant effecton the efficacy of the ligand.

These trifluoromethyl substituted compounds were also studied with animmature female rat uterotrophic growth assay; the results are shown inFIGS. 12, 13, and 14. In the estrogenic assay, the ortho-isomer producedan effect comparable to estradiol at a 3 nM level and substantialestrogenic effects at 10 and 100 nM. The meta- and para-isomers,however, demonstrated little or no estrogenic effects, even at 10 and100 nM. Therefore, the agonist responses observed in the in vitro cellproliferation assay were carried over to the intact animal as well. Theantiestrogen assay evaluated the ability of the isomers to block theuterotrophic effect induced by 1 nM estradiol. Under these conditions,the ortho isomer produced an enhancement of the estrogenic response atboth 10 and 100 nM. The meta-isomer demonstrated no significant effecton the estradiol response at either dose, however, the para isomerreduced the estrogenic response at the 100 nM level. Therefore, in bothestrogen responsive cells and tissues these new ligands are producingdifferential responses in affinity and efficacy related to the site oftrifluoromethyl substitution on the phenyl ring.

Example II

Development of Antiandrogens

The cellular target for antiandrogen therapy, the androgen receptor(AR), is a member of the nuclear receptor superfamily which has beenstudied extensively over the past decade (Tsai, 1994). Members of thisreceptor bear a strong structural similarity (homology) and utilizesimilar signaling pathways to express their biological actions. At themolecular level, the AR, like the other steroid hormone receptors, iscomposed of discrete domains that are responsible for specificfunctions. The hormone binding domain (HBD), the sequence of aminoacidsnear the N-terminus of the AR, recognizes and binds testosterone withhigh affinity but not other hormones or small endogenous molecules(Weatherman, 1999; Simons, 1998). This region of the receptor has beenexamined using X-ray crystallography to elucidate the aminoacid residuesresponsible for the recognition of specific hormones. The hormonebinding domains on the estrogen receptor (ER), progesterone receptor(PgR) and retinoic acid receptor (RAR) provide a common fold for theendogenous hormone, which also strongly suggest the types ofconformational changes that occur upon ligand binding (Brzozowski, 1997;Tannenbaum, 1998; Shiau, 1998; Williams, 1998; Renaud, 1995; Klaholz,1998). The conformational changes, particularly those associated withhelix-12, assist in the recruitment of specific coactivator proteinsthat appear to initiate the action of the general transcriptionapparatus (Resche-Rigon, 1998; McKenna, 1999; Klinge, 2000).

In accordance with the present invention, the steroidal nucleus is theaddress component, which directs the molecule to the HBD where, foragonists, the D-ring substituents direct helix-12 into a conformationthat exposes the Activation Function-2 (AF-2) or message component. Forknown ER and PgR antagonists, the steroid nucleus present in most drugsprovides the appropriate address. However, the incorporation of anadditional functional group interferes with the movement of helix-12,and produces a full or partial antagonist response (message). Most ofthe antihormones known in the art incorporate that additional functionalgroup at either the 11β- or 7α-position of the steroid (see FIG. 7). Thepresent invention shows that antagonism can be generated throughintroduction of an appropriate 17α-substituent.

Significant research efforts have focused on the synthesis andevaluation of compounds designed to either mimic or block the effects ofthe endogenous androgen, testosterone. While many steroidal compoundscan mimic testosterone, relatively few were able to block its effects intarget tissues and virtually none were effective in treating hormoneresponsive prostate cancer (Teutsch, 1995). Nonsteroidal agents,however, such as (hydroxy)flutamide, nilutamide, and bicalutamide(Sciarra, 1990; Tucker, 1988, 1990), have demonstrated clinical efficacyfor the treatment of prostatic carcinoma, even though their affinity forthe AR is relatively low when compared to testosterone (Kokontis, 1999;Battmann, 1998). Recent publications have disclosed another class ofnonsteroidal antiandrogens which have potential as clinically usefulagents (Hamann, 1998; Edwards, 1999; Higuchi, 1999; Kong, 2000). Analogsof these compounds also demonstrate agonist/antagonist responses atother nuclear receptors (Pooley, 1998; Zhi, 1998, 1999, 2000). Becausethe nonsteroidal antiandrogens do not. correspond to any current steroidhormone pharmacophore, it is possible that they may primarily effectonly the message region (helix-12) of the AR-HBD. A potent interactionat that site would still compete with agonist ligand binding for theaddress region, not entirely unlike the situation for the dopaminetransporter inhibitors where structurally diverse families of ligandsnot only inhibit dopamine and cocaine binding but also, by associatingwith overlapping sites, inhibit the binding of each other. Thus, thepresent invention combines features from both the steroid nucleus(address component) and the nonsteroidal antagonist pharmacophore(message component) (see FIG. 8).

Synthesis and Evaluation of Steroidal Antiandrogens at the 17α-Positionof Testoterone

Synthesis of the Message Components, Characterization, andConformational Analysis

A combination of organotin chemistry and palladium catalyzed couplingreactions is used for the synthesis of the message components (see FIG.10). The 1-ethynyl-1-aminoperhydroindanes which would incorporate the C-and D-rings of the steroid nucleus is prepared from the corresponding1-ethynyl-1-acetoxy analogs using a Cu(I)-assisted aminolysis. Theethynyl cycloalkyl alcohols or amines readily undergo hydrostannation togive the corresponding E- and Z-stannylvinyl intermediates which can becoupled with the requisite mono- or di-substituted aryl iodide underStille coupling conditions (Farina, 1995; Casado, 1998). Three 3′- or4′-substituted, three 3′-, 4′-disubstituted, and three 3′-,5′-disubstituted phenyl iodides are used to generate a total of 18compounds. While there are no obvious choices for the optimalsubstituents, the structure activity relationships (SAR) forantiandrogens suggest that electron withdrawing groups (e.g., —NO₂, CF₃)enhance potency. Therefore, these groups are used with one electronreleasing group in the first series (Tucker, 1988). Suzuki couplingreaction is used with vinylboronic acid (Suzuki, 1999). TheE-vinylboronic acid is accessed directly by hydroboration of the alkynewith catecholborane followed by hydrolysis. The Z-isomer is obtainedfrom the Z-vinylstannane via idododestannylation, followed by couplingwith bispinacolatodiboron, and hydrolysis.

For the synthesis of the spirocyclic ether or amine message components,the coupling partner for the Z-vinylstannane (or boronic acid) requiresan orthoiodo(bromo)phenol derivative. Halogenation of the commerciallyavailable 3′- or 4′-substituted phenol gives the intermediate which isinitially protected as the silyl ether. The Z-vinyl arene is made by thestandard Stille or Suzuki coupling methods. The conditions developed byBuchwald and Hartwig to effect the intramolecular aryl amine/etherformation may be used (Wolfe, 1998, 1999; Yang, 1999; Hartwig, 1998a,b).Deprotection of the phenol, conversion to the triflate, and couplingwith an appropriate Pd catalyst, such as Pd₂(dba)₃, and an activatingligand, such as BINAP, will effect the cyclization. The final product isprovided by the deprotection of the amine.

Each new compound synthesized is characterized by the standardspectrometric methods—high resolution mass spectrometry (HRMS),H-1/C-13-nuclear magnetic resonance spectrometry (NMR) to confirm theproposed molecular structures. Solution conformations is determined byusing 1D- and 2D-NMR techniques, methods of which are described above.The use of both conformational analysis and computational methods, moreprobable solution conformations are identified, which providesinformation with regard to key structural features and how theyinfluence molecular conformations.

Screening For Androgen Receptor Affinity, Efficacy and Selectivity

Compounds prepared containing the message components may be screened bya bioevaluation protocol already established through a commerciallyavailable company (e.g., MDS-Panlabs, located in Bothell, Wash.) todetermine their AR affinity, efficacy and selectivity. Receptors fromrat ventral prostate tissue may be used to determine the IC50 and Kivalues. [H-3] mibolerone may be used as the radioligand. Synthesizedhydroxyflutamide, nilutamide, bicalutamide and LG 120907 is evaluated asstandard AR ligands. Those new compounds that demonstrate ARaffinities >10% that of bicalutamide or LG 120907 will be evaluated fortheir affinities for the other nuclear receptors. Other sources forreceptors and their radioligands include Erα-human recombinant frominsect St9 cells, [H-3] estradiol, GR-human Jerkat cells, [H-3]dexamethasone, and PgR-bovine, [H-3]R-5020. Compounds that express asignificant selectivity for AR (>10:1) is tested for their efficacy inthe rat agonism/antagonism model. In vitro efficacy model for testingthe compounds for antagonism is the use of cotransfection and whole cellreceptor binding (Hamann, 1998).

Preliminary SARs is determined from the IC50 and Ki data from thescreening of the new compounds. E- vs. Z-stereochemistry of the acyclicseries of compounds is studied as well as the effects of mono- vs.di-substitution and 3- vs. 4-substitution. The cyclized compounds arecompared with the acyclic series to identify particular substituenttrends. The QSAR-CoMFA module of SYBIL is used to clarify the individualparameters (Gantchev, 1994). The physicochemical parameters developed byHansch may also be used to evaluate the data (Gantchev, 1994). The mostpotent ligands are analyzed for the lowest energy conformations usingQUANTA-CHARMM/mm3 force fields (Wurtz, 1998) and compared with thosefrom the NMR conformational studies to rationalize the initial SAR. Thisallows for better determination of which substituents are most effectivein contributing to AR affinity, selectivity and antihormonal response.Subsequently, the selected substituents is used for incorporation intothe address-message composite.

Synthesis of (Nor)Testosterone Derivatives With the Message Component at17α-Position

17α-ethynyl-(19nor)testoterone and its dihydroderivative (addresscomponent) is used as the starting material. The message components maybe obtained from commercially available (or readily synthesized) mono-and disubstituted iodophenols. The same message components as with theestrogen study are used—the nilutamide/bicalutamide family ofnonsteroidal antagonists and the more potent Ligand Pharmaceuticalantagonists. For the message components analogous to flutamide andbicalutamide, the ethylene group is selected as an isostericsubstitution for the amide bond (Luthman, 1996). The method forsynthesis of the (nor)testosterone derivatives with the messagecomponent at the 17α-position is similar to the steps used for thesynthesis of antiestrogens described herein. The antiandrogens of thepresent invention will include the steroid nucleus (A-D rings) and willprovide functionality in the A-ring (3 C═O/—OH; 4,5-C═C). As anembodiment, these groups are prepared to protect them as ketals, estersor silyl/enol ethers (Hoyte, 1993; van den Bos, 1998).

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While the present invention has been described in conjunction with apreferred embodiment, one of ordinary skill, after reading the foregoingspecification, will be able to effect various changes, substitutions ofequivalents, and other alterations to the compositions and approachesset forth herein. It is therefore intended that the protection grantedby Letters Patent hereon be limited only by the definitions contained inthe appended claims and equivalents thereof.

1-21. (canceled)
 22. A therapeutic composition for prophylaxis ortreatment of an estrogen or androgen mediated disorder, said compositioncomprising: a compound having the structural formula, wherein saidcompound has a message unit at the 17α-position of an address unit,comprising either: an address unit having the structure:

wherein: R¹ is H, CH₃, CH₂CH₃, OH, OCH₃, OCH₂CH₃, C₁-C₆ alkyl, CH═CH₂,CH═CHCH₃, CH₂-aryl; R² is H, CH₃, COCH₃, CO(CH₂)_(n)CH₃, CO-aryl, alkyl,cycloalkyl (ether), ester; and R³ is H, CH₃, CH₂CH₃, aryl, heteroaryl,C₁-C₆ alkyl, alkyl (C₁-C₆) amides, alkyl (C₁-C₆) sulfide, alkyl (C₁-C₆)sulfone, alkyl (C₁-C₆) sulfoxide; and a message unit having thestructure:

wherein: R⁴ is H, C₁-C₄ alkyl; R⁵ is substituted aryl, heteroaryl, fusedaryl, —CO-aryl, CO-fused aryl, —CO-heteroaryl, —CO-fused heteroaryl,biaryl, CO-biaryl, ether-linked aryls, ether-linked heteroaryls,amine-linked aryls, amine-linked heteroaryls, aminoalkoxy arene hybrid,or peptidyl hybrid, wherein any substituted aryl, heteroaryl, fusedaryl, —CO-aryl, CO-fused aryl, —CO-heteroaryl, —CO-fused heteroaryl,biaryl, CO-biaryl, ether-linked aryls, ether-linked heteroaryls,amine-linked aryls, amine-linked heteroaryls, aminoalkoxy arene hybridand peptidyl hybrid, may optionally be substituted, independently, withH, CH₃, OH, OCH₃, OCF₃, N(CH₃)₂, NHCOCH₃, aryl, CO₂CH₃, CONH₂, C₁-C₄alkyl, (CF₂)_(n)F wherein n=1-4, Cl, Br, I, F, O(CH₂)_(n)H whereinn=1-4, NO₂, NH₂, NHCOR⁴, CO₂H, CO₂R⁴, CONHR⁴, amyl, thioether, SR⁶,S(O)R⁶, SO₂R⁶, SO₂NR⁶R⁷; wherein R⁴ has the definition given above;wherein R⁶ is H, C₁-C₄ alkyl or perfluoroalkyl, aryl, heteroaryl,optionally substituted allyl, arylmethyl, alkynyl, or alkenyl; whereinR⁷ is H, C₁-C₄ alkyl or perfluoroalkyl, aryl, heteroaryl, optionallysubstituted allyl, arylmethyl, OR⁸ or NHR⁸; wherein R⁸ is H, C₁-C₆ alkylor perfluoroalkyl, aryl, heteroaryl, optionally substituted allyl,arylmethyl, SO₂R⁶ or S(O)R⁶, wherein R⁶ has the definition given above,wherein R⁵ can be in either the E or Z configuration in relation to the17α-position of said address unit; or an address unit having one of thefollowing different structures:

wherein: R¹⁰ is H, CH₃; R¹¹ is H, C₁-C₄ alkyl; R¹² is O, (H, OH); R¹³ isH, OH, Cl, Br, I, CH₃; R¹⁴ is H, C₁-C₄ alkyl; R is O, (H, OH); R¹⁶ is O,NH; and R¹⁷ through R¹⁸ each independently is H, CH₃; and a message unithaving the structure:

wherein: R⁴ is H, C₁-C₄ alkyl; R⁵ is aryl, heteroaryl, fused aryl,—CO-aryl, CO-fused aryl, —CO-heteroaryl, —CO-fused heteroaryl, biaryl,CO-biaryl, ether-linked aryls, ether-linked heteroaryls, amine-linkedaryls, or amine-linked heteroaryls, wherein any aryl, heteroaryl, fusedaryl, —CO-aryl, CO-fused aryl, —CO-heteroaryl, —CO-fused heteroaryl,biaryl, CO-biaryl, ether-linked aryls, ether-linked heteroaryls,amine-linked aryls, and amine-linked heteroaryls may optionally besubstituted, independently, with H, CH₃, OH, OCH₃, OCF₃, N(CH₃)₂,NHCOCH₃, aryl, CO₂CH₃, CONH₂, C₁-C₄ alkyl, (CF₂)_(n)F wherein n=1-4, Cl,Br, I, F, O(CH₂)_(n)H wherein n=1-4, NO₂, NH₂, NHCOR⁴, CO₂H, CO₂R⁴,CONHR⁴, amyl, thioether, SR⁶, S(O)R⁶, SO₂R⁶, SO₂NR⁶R⁷; wherein R⁴ hasthe definition given above; wherein R⁶ is H, C₁-C₄ alkyl orperfluoroalkyl, aryl, heteroaryl, optionally substituted allyl,arylmethyl, alkynyl, or alkenyl; wherein R⁷ is H, C₁-C₄ alkyl or perfluoroalkyl, aryl, heteroaryl, optionally substituted allyl, arylmethyl,OR⁸ or NHR⁸; wherein R⁸ is H, C₁-C₆ alkyl or perfluoroalkyl, aryl,heteroaryl, optionally substituted allyl, arylmethyl, SO₂R⁶ or S(O)R⁶,wherein R⁶ has the definition given above, wherein R⁵ can be in eitherthe E or Z configuration in relation to the 17α-position of the addressunit; said compound in a pharmaceutically acceptable inert carriersubstance, wherein said compound is capable of binding to a hormonereceptor.
 23. The composition of claim 22, wherein said hormone receptoris an estrogen receptor.
 24. The composition of claim 22, wherein saidhormone receptor is an androgen receptor.
 25. The composition of claim22, wherein the composition is formulated for oral, topical,intravenous, intramuscular, subcutaneous, intra-vaginal, suppository orparenteral administration.
 26. A method of preventing or treating apatient suffering from or believed to be at risk of suffering from anestrogen or androgen mediated disorder, said method comprising the stepsof: providing said patient; and administering to said patient aneffective amount of the therapeutic composition of claim 22, whereinsaid amount of said composition is effective in preventing or treatingsaid estrogen or androgen mediated disorder.
 27. The method of claim 26,wherein said estrogen or androgen mediated disorder is osteoporosis,endometriosis, breast cancer, benign breast cancer, uterine cancer,ovarian cancer, polycystic ovarian disease, prostate cancer, benignprostatic hyperplasia, reduction of cardiac diseases, acne, seborrhea,alopecia, hirsutism, male pattern baldness, or infertility.
 28. Themethod of claim 26, wherein said patient is human.
 29. The method ofclaim 26, wherein said composition is administered to said patient as adosage unit from about 0.1 μg/kg/day to 10 μg/kg/day.
 30. The method ofclaim 26, wherein said composition is administered to said patient as adosage unit from about 0.5 μg/kg/day to 5 μg/kg/day.
 31. The method ofclaim 26, wherein said composition is administered to said patient as adosage unit from about 1 μg to 100 μg by local administration.
 32. Themethod of claim 26, wherein said composition is administered to saidpatient as a dosage unit from about 0.10 mg/kg/day to about 40mg/kg/day.
 33. The method of claim 26, wherein said composition isadministered to said patient as a dosage unit from about 0.50 mg/kg/dayto about 20 mg/kg/day.
 34. The method of claim 26, wherein saidcomposition is administered to said patient as a dosage unit from about1.0 mg/kg/day to about 10 mg/kg/day.
 35. A kit comprising a therapeuticcomposition of claim 22 and instructions for use thereof.
 36. A methodfor the prophylaxis or treatment of a prostate disorder in a patient,said method comprising the steps of: providing a patient suffering fromor believed to be at risk of developing a prostate disorder;administering to said patient an effective amount of a compound havingthe structural formula: an address unit having one of the followingdifferent structures:

wherein R¹⁰ is H, CH₃; R¹¹ is H, C₁-C₄ alkyl; R¹² is O, (H, OH); R¹³ isH, OH, Cl, Br, I, CH₃; R¹⁴ is H, C₁-C₄ alkyl; R¹⁵ is O, (H, OH); R¹⁶ isO, NH; and R¹⁷ through R¹⁸ each independently is H, CH₃; and a messageunit having the structure:

wherein: R⁴ is H, C₁-C₄ alkyl; R⁵ is aryl, heteroaryl, fused aryl,—CO-aryl, CO-fused aryl, —CO-heteroaryl, —CO-fused heteroaryl, biaryl,CO-biaryl, ether-linked aryls, ether-linked heteroaryls, amine-linkedaryls, or amine-linked heteroaryls, wherein any aryl, heteroaryl, fusedaryl, —CO-aryl, CO-fused aryl, —CO-heteroaryl, —CO-fused heteroaryl,biaryl, CO-biaryl, ether-linked aryls, ether-linked heteroaryls,amine-linked aryls, and amine-linked heteroaryls may optionally besubstituted, independently, with H, CH₃, OH, OCH₃, OCF₃, N(CH₃)₂,NHCOCH₃, aryl, CO₂CH₃, CONH₂, C₁-C₄ alkyl, (CF₂)_(n)F wherein n=1-4, Cl,Br, I, F, O(CH₂)_(n)H wherein n=1-4, NO₂, NH₂, NHCOR⁴, CO₂H, CO₂R⁴,CONHR⁴, amyl, thioether, SR⁶, S(O)R⁶, SO₂R⁶, SO₂NR⁶R⁷; wherein R⁴ hasthe definition given above; wherein R⁶ is H, C₁-C₄ alkyl or perfluoroalkyl, aryl, heteroaryl, optionally substituted allyl, arylmethyl,alkynyl, or alkenyl; wherein R⁷ is H, C₁-C₄ alkyl or perf luoroalkyl,aryl, heteroaryl, optionally substituted allyl, arylmethyl, OR⁸ or NHR⁸;wherein R⁸ is H, C₁-C₆ alkyl or perfluoroalkyl, aryl, heteroaryl,optionally substituted allyl, arylmethyl, SO₂R⁶ or S(O)R⁶, wherein R⁶has the definition given above, wherein R⁵ can be in either the E or Zconfiguration in relation to the 17α-position of the address unit. 37.The method of claim 36, wherein said compound binds to the androgenreceptor.
 38. The method of claim 36, wherein said prostate disorder isprostate cancer, prostate carcinoma, or benign prostate hyperplasia. 39.An article of manufacture comprising packaging material and atherapeutic composition contained within said packaging material;wherein said therapeutic composition is therapeutically effective forprophylaxis or treatment of an estrogen or androgen mediated disorder;wherein said packaging material comprises a label with instructions thatindicates that the therapeutic composition can be used for prophylaxisor treatment an estrogen or androgen mediated disorder; and wherein saidtherapeutic composition is the composition of claim
 22. 40. The articleof manufacture of claim 39, wherein said estrogen or androgen mediateddisorder is osteoporosis, endometriosis, breast cancer, benign breastcancer, uterine cancer, ovarian cancer, polycystic ovarian disease,prostate cancer, benign prostatic hyperplasia, reduction of cardiacdiseases, acne, seborrhea, alopecia, hirsutism, male pattern baldness,or infertility.
 41. An article of manufacture comprising packagingmaterial and a therapeutic composition contained within said packagingmaterial; wherein said therapeutic composition is therapeuticallyeffective for treatment of osteoporosis, endometriosis, breast cancer,benign breast cancer, uterine cancer, ovarian cancer, polycystic ovariandisease, prostate cancer, benign prostatic hyperplasia, reduction ofcardiac diseases, acne, seborrhea, alopecia, hirsutism, male patternbaldness, or infertility; wherein said packaging material comprises alabel with instructions that indicates that the therapeutic compositioncan be used for treatment of osteoporosis, endometriosis, breast cancer,benign breast cancer, uterine cancer, ovarian cancer, polycystic ovariandisease, prostate cancer, benign prostatic hyperplasia, reduction ofcardiac diseases, acne, seborrhea, alopecia, hirsutism, male patternbaldness, or infertility; and wherein said therapeutic composition isthe composition of claim
 22. 42. A method of preventing or treating apatient suffering from or believed to be at risk of suffering fromosteoporosis, endometriosis, breast cancer, benign breast cancer,uterine cancer, ovarian cancer, polycystic ovarian disease, prostatecancer, benign prostatic hyperplasia, reduction of cardiac diseases,acne, seborrhea, alopecia, hirsutism, male pattern baldness, orinfertility, said method comprising the steps of: providing saidpatient; and administering to said patient an effective amount of thetherapeutic composition of claim 22, wherein said amount of saidcomposition is effective in preventing or treating osteoporosis,endometriosis, breast cancer, benign breast cancer, uterine cancer,ovarian cancer, polycystic ovarian disease, prostate cancer, benignprostatic hyperplasia, reduction of cardiac diseases, acne, seborrhea,alopecia, hirsutism, male pattern baldness, or infertility.